My ultimate objective is to develop a quantitative systems analysis of not only the short-term but also the long-term physiological mechanisms that control plasma volume and extracellular fluid volume. Understanding the regulation of these demands a knowledge of the factors that control the partition of fluid between the vascular compartment and the interstitium, which in turn, requires an understanding of how these factors affect the balance of Starling forces across the capillary membrane. The four Starling forces are 1) capillary hydrostatic pressure, 2) interstitial fluid hydrostatic pressure, 3) plasma colloid osmotic pressure, and 4) interstitial fluid colloid osmotic pressure. My chronic studies have shown that either moderate decreases or increases in plasma protein concentration cause no measurable change in plasma volume, but the reasons for these surprising results are not yet known. Therefore, I plan to measure each of the Starling forces as well as the plasma concentrations of catecholamines, angiotensin II (AII), and antidiuretic hormone (ADH) in long-term experiments on both hypoproteinemia and hyperproteinemia. In particular, the contributions to the maintenance of plasma volume during changes in plasma protein concentration by the following two mechanisms will be determined: 1) changes in interstitial fluid colloid osmotic pressure and 2) alteration in capillary hydrostatic pressure due to changes in the plasma concentrations of catecholamines, AII, and ADH. Another factor that also can affect the extracellular distribution of protein and fluids is the capillary permeability to protein. I will therefore determine the separate effects of plasma protein concentration and AII on capillary permeability. Yet another major factor contributing to the regulation of extracellular fluid volume is the renal excretion of sodium and water. My studies have shown a significant effect of hypoproteinemia on renal function; therefore, I will also study the chronic effects of hyperproteinemia on renal hemodynamics, sodium and water balance, hormonal changes, and the relationship between arterial pressure and renal sodium and water output. Altogether, these studies will describe the roles of the systemic circulation, micro-circulation, and interstitium in extracellular fluid volume regulation. Therefore, our understanding of pathological states such as hypertension, shock, edema, congestive heart failure, nephrosis, Kwashiorkor, and cirrhosis of the liver will be markedly enhanced.